tbuckley/cabot-search huggingface dataset:
Root-cause Analysis of 762 Danish Post-colonoscopy Colorectal Cancer Patients
Authors: Frederikke Schønfeldt Troelsen, Henrik Toft Sørensen, Lars Pedersen, Lone Dragnes Brix, Louise Bang Grode, Evelien Dekker, Rune Erichsen
Journal: Clinical Gastroenterology and Hepatology (2023)

The term post-colonoscopy colorectal cancer (PCCRC) refers to colorectal cancer (CRC) diagnosed after a negative colonoscopy. Using the root-cause algorithm proposed by the World Endoscopy Organization, we aimed to investigate plausible explanations for PCCRCs and potential changes in plausible explanations for PCCRCs over time in a Danish Region.During 1995 to 2021, we used national health registries and electronic medical records in the Central Denmark Region to identify PCCRC cases, defined as CRCs recorded within 6 to 48 months after a colonoscopy. We then applied the World Endoscopy Organization algorithm to categorize explanations for PCCRC as follows: (A) possible missed lesion, prior examination adequate; (B) possible missed lesion, prior examination inadequate; (C) detected lesion, not resected; or (D) likely incomplete resection of previously identified lesion. PCCRCs were identified before (1995-2013) and after (2014-2021) implementation of nationwide fecal immunochemical test-based CRC screening and quality indicators for colonoscopy.We identified 762 PCCRCs, 53.5% among males and 57% among individuals ≥70 years. Forty-five percent were located in the proximal colon. We identified 616 (80.8%; 95% confidence interval [CI], 74.6%-87.5%) category A PCCRCs; 36 (4.7%; 95% CI, 3.3%-6.5%) category B PCCRCs; 26 (3.4%; 95% CI, 2.2%-4.9%) category C PCCRCs; and 84 (11%; 95% CI, 8.8%-13.6%) category D PCCRCs. Similar patterns were observed during the early (1995-2013) and late (2014-2021) study periods.Most PCCRCs originate from possible missed lesions and incompletely resected lesions during the complete study period. These findings indicate the importance of quality assurance of colonoscopy procedures and polypectomy techniques.
Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk
Authors: Kasper A. Overbeek, Brechtje D.M. Koopmann, Iris J.M. Levink, Matteo Tacelli, Nicole S. Erler, Paolo Giorgio Arcidiacono, Margreet G.E. Ausems, Anja Wagner, Casper H. van Eijck, Bas Groot Koerkamp, Olivier R. Busch, Marc G. Besselink, Manon van der Vlugt, Lydi M.J.W. van Driel, Paul Fockens, Frank P. Vleggaar, Jan-Werner Poley, Gabriele Capurso, Djuna L. Cahen, Marco J. Bruno
Journal: Clinical Gastroenterology and Hepatology (2023)

In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs.
Comparative Effectiveness of Upadacitinib and Tofacitinib in Inducing Remission in Ulcerative Colitis: Real-World Data
Authors: Leo Boneschansker, Ashwin N. Ananthakrishnan, Kristin E. Burke, Bharati D. Kochar, Emily W. Lopes, Hamed Khalili, Francis Colizzo
Journal: Clinical Gastroenterology and Hepatology (2023)
Computational prediction of MHC anchor locations guides neoantigen identification and prioritization
Authors: Huiming Xia, Joshua McMichael, Michelle Becker-Hapak, Onyinyechi C. Onyeador, Rico Buchli, Ethan McClain, Patrick Pence, Suangson Supabphol, Megan M. Richters, Anamika Basu, Cody A. Ramirez, Cristina Puig-Saus, Kelsy C. Cotto, Sharon L. Freshour, Jasreet Hundal, Susanna Kiwala, S. Peter Goedegebuure, Tanner M. Johanns, Gavin P. Dunn, Antoni Ribas, Christopher A. Miller, William E. Gillanders, Todd A. Fehniger, Obi L. Griffith, Malachi Griffith
Journal: Science Immunology (2023)

Neoantigens are tumor-specific peptide sequences resulting from sources such as somatic DNA mutations. Upon loading onto major histocompatibility complex (MHC) molecules, they can trigger recognition by T cells. Accurate neoantigen identification is thus critical for both designing cancer vaccines and predicting response to immunotherapies. Neoantigen identification and prioritization relies on correctly predicting whether the presenting peptide sequence can successfully induce an immune response. Because most somatic mutations are single-nucleotide variants, changes between wild-type and mutated peptides are typically subtle and require cautious interpretation. A potentially underappreciated variable in neoantigen prediction pipelines is the mutation position within the peptide relative to its anchor positions for the patient's specific MHC molecules. Whereas a subset of peptide positions are presented to the T cell receptor for recognition, others are responsible for anchoring to the MHC, making these positional considerations critical for predicting T cell responses. We computationally predicted anchor positions for different peptide lengths for 328 common HLA alleles and identified unique anchoring patterns among them. Analysis of 923 tumor samples shows that 6 to 38% of neoantigen candidates are potentially misclassified and can be rescued using allele-specific knowledge of anchor positions. A subset of anchor results were orthogonally validated using protein crystallography structures. Representative anchor trends were experimentally validated using peptide-MHC stability assays and competition binding assays. By incorporating our anchor prediction results into neoantigen prediction pipelines, we hope to formalize, streamline, and improve the identification process for relevant clinical studies.
Anaplastic Classic Kaposi Sarcoma: PD-L1 Expression and Response to Immunotherapy: A Case Report and Review of the Literature
Authors: Ivan Lolli, Anna Maria Valentini, Angela Dalia Ricci, Raffaele Armentano
Journal: Journal of the National Comprehensive Cancer Network (2023)

Anaplastic classic Kaposi sarcoma (CKS) is an extremely rare pathologic variant of CKS characterized by high aggressiveness and poor prognosis. We report the clinical course of this malignant histologic form in an otherwise healthy 67-year-old male from Apulia in Southern Italy. The anaplastic progression arose during a long history of CKS and developed after multiple local and systemic treatments. The extremely aggressive and chemorefractory nature of the disease dictated amputation of a lower limb and, later, surgery for metastatic pulmonary involvement. At subsequent relapse, therapy with the anti–PD-1 inhibitor pembrolizumab was started. The immunotherapy was selected based on the PD-L1 expression in the tumor and tumor microenvironment. Remarkably, PD-1 blockade induced a complete and durable response in the patient, with a disease-free survival that has exceeded 18 months, and follow-up is still ongoing.
Head-to-head Comparison of the Diagnostic Accuracy of Prostate-specific Membrane Antigen Positron Emission Tomography and Conventional Imaging Modalities for Initial Staging of Intermediate- to High-risk Prostate Cancer: A Systematic Review and Meta-analysis
Authors: Kit Mun Chow, Wei Zheng So, Han Jie Lee, Alvin Lee, Dominic Wei Ting Yap, Yemisi Takwoingi, Kae Jack Tay, Jeffrey Tuan, Sue Ping Thang, Winnie Lam, John Yuen, Nathan Lawrentschuk, Michael S. Hofman, Declan G. Murphy, Kenneth Chen
Journal: European Urology (2023)
National Physician-Level Endophthalmitis Rates for Cataract Surgery among Medicare Beneficiaries in the United States: 2011–2019
Authors: Sidra Zafar, Chen Dun, Divya Srikumaran, Cindy X. Cai, Peiqi Wang, Oliver D. Schein, Martin Makary, Fasika Woreta
Journal: Ophthalmology (2023)
Sebaceous carcinoma epidemiology, associated malignancies and Lynch/Muir-Torre syndrome screening in England from 2008 to 2018
Authors: Sam Cook, Joanna Pethick, Nour Kibbi, Loes Hollestein, Katrina Lavelle, Isabella de Vere Hunt, Clare Turnbull, Brian Rous, Akhtar Husain, John Burn, Margreet Lüchtenborg, Francesco Santaniello, Fiona McRonald, Steven Hardy, Eleni Linos, Zoe Venables, Neil Rajan
Journal: Journal of the American Academy of Dermatology (2023)

Sebaceous carcinomas (SC) may be associated with the cancer predisposition syndrome Muir-Torre/Lynch syndrome (MTS/LS), identifiable by SC mismatch repair (MMR) screening; however, there is limited data on MMR status of SC.To describe the epidemiology of SC, copresentation of other cancers, and population level frequency of MMR screening in SC.A population-based retrospective cohort study of SC patients in the National Cancer Registration and Analysis Service in England.This study included 1077 SC cases (739 extraocular, 338 periocular). Age-standardized incidence rates (ASIR) were higher in men compared with women, 2.74 (95% CI, 2.52-9.69) per 1,000,000 person-years for men versus 1.47 person-years (95% CI, 1.4-1.62) for women. Of the patients, 19% (210/1077) developed at least one MTS/LS-associated malignancy. MMR immunohistochemical screening was performed in only 20% (220/1077) of SC tumors; of these, 32% (70/219) of tumors were MMR deficient.Retrospective design.Incorporation of MMR screening into clinical practice guidelines for the management of SC will increase the opportunity for MTS/LS diagnoses, with implications for cancer surveillance, chemoprevention with aspirin, and immunotherapy treatment targeted to MTS/LS cancers.
Guideline-based intervention improves the quality of antibiotic allergy registration in a hospital setting
Authors: Chiara van der Worp, Tara Middeldorp, Laura Kuijpers, Jonna Bank, Lisa Dol, Martha van der Beek, Esther J. van Zuuren, Bart Hendriks, Leo Visser, Mark de Boer, Merel Lambregts
Journal: Clinical Microbiology and Infection (2023)
Pirfenidone in fibrotic hypersensitivity pneumonitis: a double-blind, randomised clinical trial of efficacy and safety
Authors: Evans R Fernández Pérez, James L Crooks, David A Lynch, Stephen M Humphries, Tilman L Koelsch, Jeffrey J Swigris, Joshua J Solomon, Michael P Mohning, Steve D Groshong, Kaitlin Fier
Journal: Thorax (2023)

Fibrotic hypersensitivity pneumonitis (FHP) is an irreversible lung disease with high morbidity and mortality. We sought to evaluate the safety and effect of pirfenidone on disease progression in such patients.We conducted a single-centre, randomised, double-blinded, placebo-controlled trial in adults with FHP and disease progression. Patients were assigned in a 2:1 ratio to receive either oral pirfenidone (2403 mg/day) or placebo for 52 weeks. The primary end point was the mean absolute change in the per cent predicted forced vital capacity (FVC%). Secondary end points included progression-free survival (PFS, time to a relative decline ≥10% in FVC and/or diffusing capacity of the lung for carbon monoxide (DLCO), acute respiratory exacerbation, a decrease of ≥50 m in the 6 min walk distance, increase or introduction of immunosuppressive drugs or death), change in FVC slope and mean DLCO%, hospitalisations, radiological progression of lung fibrosis and safety.After randomising 40 patients, enrolment was interrupted by the COVID-19 pandemic. There was no significant between-group difference in FVC% at week 52 (mean difference -0.76%, 95% CI -6.34 to 4.82). Pirfenidone resulted in a lower rate of decline in the adjusted FVC% at week 26 and improved PFS (HR 0.26, 95% CI 0.12 to 0.60). Results for other secondary end points showed no significant difference between groups. No deaths occurred in the pirfenidone group and one death (respiratory) occurred in the placebo group. There were no treatment-emergent serious adverse events.The trial was underpowered to detect a difference in the primary end point. Pirfenidone was found to be safe and improved PFS in patients with FHP.NCT02958917.
Identification of a broadly fibrogenic macrophage subset induced by type 3 inflammation
Authors: Thomas Fabre, Alexander M. S. Barron, Stephen M. Christensen, Shoh Asano, Kathryn Bound, Matthew P. Lech, Marc H. Wadsworth, Xiao Chen, Chang Wang, Ju Wang, James McMahon, Franklin Schlerman, Alexis White, Kellie M. Kravarik, Andrew J. Fisher, Lee A. Borthwick, Kevin M. Hart, Neil C. Henderson, Thomas A. Wynn, Ken Dower
Journal: Science Immunology (2023)

Macrophages are central orchestrators of the tissue response to injury, with distinct macrophage activation states playing key roles in fibrosis progression and resolution. Identifying key macrophage populations found in human fibrotic tissues could lead to new treatments for fibrosis. Here, we used human liver and lung single-cell RNA sequencing datasets to identify a subset of CD9+TREM2+ macrophages that express SPP1, GPNMB, FABP5, and CD63. In both human and murine hepatic and pulmonary fibrosis, these macrophages were enriched at the outside edges of scarring and adjacent to activated mesenchymal cells. Neutrophils expressing MMP9, which participates in the activation of TGF-β1, and the type 3 cytokines GM-CSF and IL-17A coclustered with these macrophages. In vitro, GM-CSF, IL-17A, and TGF-β1 drive the differentiation of human monocytes into macrophages expressing scar-associated markers. Such differentiated cells could degrade collagen IV but not collagen I and promote TGF-β1-induced collagen I deposition by activated mesenchymal cells. In murine models blocking GM-CSF, IL-17A or TGF-β1 reduced scar-associated macrophage expansion and hepatic or pulmonary fibrosis. Our work identifies a highly specific macrophage population to which we assign a profibrotic role across species and tissues. It further provides a strategy for unbiased discovery, triage, and preclinical validation of therapeutic targets based on this fibrogenic macrophage population.
Human T follicular helper clones seed the germinal center–resident regulatory pool
Authors: Carole Le Coz, Derek A. Oldridge, Ramin S. Herati, Nina De Luna, James Garifallou, Emylette Cruz Cabrera, Jonathan P. Belman, Dana Pueschl, Luisa V. Silva, Ainsley V. C. Knox, Whitney Reid, Samuel Yoon, Karen B. Zur, Steven D. Handler, Hakon Hakonarson, E. John Wherry, Michael Gonzalez, Neil Romberg
Journal: Science Immunology (2023)

The mechanisms by which FOXP3+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA/TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate Treg-to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38+, germinal center-resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38- nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.
<i>β</i>−Arrestins: Structure, Function, Physiology, and Pharmacological Perspectives
Authors: Jürgen Wess, Antwi-Boasiako Oteng, Osvaldo Rivera-Gonzalez, Eugenia V. Gurevich, Vsevolod V. Gurevich
Journal: Pharmacological Reviews (2023)

The two beta-arrestins, beta-arrestin-1 and -2 (systematic names: arrestin-2 and -3, respectively), are multifunctional intracellular proteins that regulate the activity of a very large number of cellular signaling pathways and physiological functions. The two proteins were discovered for their ability to disrupt signaling via G protein-coupled receptors (GPCRs) via binding to the activated receptors. However, it is now well recognized that both beta-arrestins can also act as direct modulators of numerous cellular processes via either GPCR-dependent or -independent mechanisms. Recent structural, biophysical, and biochemical studies have provided novel insights into how beta-arrestins bind to activated GPCRs and downstream effector proteins. Studies with beta-arrestin mutant mice have identified numerous physiological and pathophysiological processes regulated by beta-arrestin-1 and/or -2. Following a brief summary of recent structural studies, this review will primarily focus on beta-arrestin-regulated physiological functions, with particular focus on the central nervous system and the roles of beta-arrestins in carcinogenesis and key metabolic processes including the maintenance of glucose and energy homeostasis. This review will also highlight potential therapeutic implications of these studies and discuss strategies that could prove useful for targeting specific beta-arrestin-regulated signaling pathways for therapeutic purposes. <b>Significance Statement</b> The two beta-arrestins, structurally closely related intracellular proteins that are evolutionarily highly conserved, have emerged as multifunctional proteins able to regulate a vast array of cellular and physiological functions. The outcome of studies with beta-arrestin mutant mice and cultured cells, complemented by novel insights into beta-arrestin structure and function, should pave the way for the development of novel classes of therapeutically useful drugs capable of regulating specific beta-arrestin functions.
Risk and accuracy of outpatient-identified hypoxaemia for death among suspected child pneumonia cases in rural Bangladesh: a multifacility prospective cohort study
Authors: Eric D McCollum, Salahuddin Ahmed, Arunangshu D Roy, ASMD Ashraful Islam, Holly B Schuh, Carina King, Shubhada Hooli, Mohammad Abdul Quaiyum, Amy Sarah Ginsburg, William Checkley, Abdullah H Baqui, Tim Colbourn
Journal: The Lancet Respiratory Medicine (2023)
The effect of early childhood respiratory infections and pneumonia on lifelong lung function: a systematic review
Authors: Andrew J Collaro, Margaret S McElrea, Julie M Marchant, Mark D Chatfield, Peter Sondergeld, Jennifer L Perret, Don Vicendese, Wanaporn Anuntaseree, Shyamali C Dharmage, Anne B Chang
Journal: The Lancet Child & Adolescent Health (2023)
Biotin receptor-mediated intracellular delivery of synthetic polypeptide-protein complexes
Authors: H. Li, G. Bruce, N. Childerhouse, G. Keegan, G. Mantovani, S. Stolnik
Journal: Journal of Controlled Release (2023)

Pulmonary delivery offers a non-invasive route for the administration of biotherapeutics. In this context, understanding and control of a transport into, and across cellular barriers is central to the design of delivery systems. Here, we report our study on receptor mediated delivery of protein cargo by a formulation comprising sub-300 nm sized non-covalent protein complexes with biotin-conjugated PEG-poly(glutamic acid) (biotin-PEG2k-b-GA10) and PEG2k-b-GA30 copolymers blend as targeting and complexing functionalities. Designed complexes achieve intracellular delivery of the cargo in lung derived A549 epithelial cells in vitro via sodium-dependent multivitamin transporter (biotin receptor). We further show that biotin receptor driven endocytosis preferentially involves dynamin- and caveolae-dependent vesicular internalization, switching the transport pathway away from predominantly clathrin-dependent entry of free protein. Significantly for a protective intracellular delivery of biotherapeutics based on non-covalent complexation with polymeric excipients, the study provides evidence of intracellular presence of the complexing copolymer; demonstrated exploiting biotin in biotin-PEG2k-b-GA10 copolymer as a tag for binding with fluorescently labelled avidin. Moreover, analysis of intracellular localization of constitutive species shortly following cellular internalization suggests a co-localization of biotin-PEG2k-b-GA10 copolymer and protein constitutive species. The study demonstrates intracellular delivery of biotin targeted non-covalent complexes with a protein cargo, the result with important implications in a design of enabling technology platforms for protective, receptor mediated intracellular delivery of biotherapeutics.
Is fat the future for saving sight? Bioactive lipids and their impact on glaucoma
Authors: Miriam Kolko, Zaynab Ahmad Mouhammad, Barbara Cvenkel
Journal: Pharmacology & Therapeutics (2023)

Glaucoma is characterized by a continuous loss of retinal ganglion cells. The cause of glaucoma is associated with an increase in intraocular pressure (IOP), but the underlying pathophysiology is diverse and, in most cases, unknown. There is an indisputable unmet need to identify new pathways involved in glaucoma pathogenesis. Increasing evidence suggests that bioactive lipids may be critical in the development and progression of glaucoma. Preclinical and clinical bioactive lipid targets exist and are being developed. In this review, we aim to shed light on the potential of bioactive lipids for the prevention, diagnosis, prognosis, and treatment of glaucoma by asking the question “is fat the future for saving sight”.
Collagen‐Based Dissolving Microneedles with Flexible Pedestals: A Transdermal Delivery System for Both Anti‐Aging and Skin Diseases
Authors: Hongqian Lv, Nan Gao, Qixin Zhou, Yan Wang, Guixia Ling, Peng Zhang
Journal: Advanced Healthcare Materials (2023)

Biocompatible polymer microneedles (MNs) are emerging as a promising platform for transdermal drug delivery, especially for facial treatments. Therefore, an MN patch in this study uses hydrolyzed collagen (HC) contained in skin cells as the main raw material and adopts a two-step cast method to develop a rapidly dissolving microneedle (DMN) to deliver collagen in a simple and minimally invasive way, allowing the release of the encapsulated drug in the skin. By optimizing the formulation and proportion of HC and auxiliary support materials, the mechanical strength required to pierce the skin is obtained, while the soft pedestal allows for flexibility in application. The DMNs can dissolve completely in the skin within 15 min and release within ≈ 8 h, and do not cause toxicity or irritation when being applied. In contrast to the ineffectiveness of oral and external application, and the high risk of dermal injection, drug-loaded DMNs overcome the drawbacks of traditional methods with direct penetration and minimally invasive manner, enabling efficient and safe treatment. The successful preparation and research of HC DMNs have innovative and practical significance in this field, and it is expected to become a simple, effective, and popular transdermal drug delivery platform for cosmetics.
High-throughput screens identify a lipid nanoparticle that preferentially delivers mRNA to human tumors in vivo
Authors: Sebastian G. Huayamares, Melissa P. Lokugamage, Regina Rab, Alejandro J. Da Silva Sanchez, Hyejin Kim, Afsane Radmand, David Loughrey, Liming Lian, Yuning Hou, Bhagelu R. Achyut, Annette Ehrhardt, Jeong S. Hong, Cory D. Sago, Kalina Paunovska, Elisa Schrader Echeverri, Daryll Vanover, Philip J. Santangelo, Eric J. Sorscher, James E. Dahlman
Journal: Journal of Controlled Release (2023)